2026年 · 第139卷第07期

Mitochondrial homeostasis is regulated by processes such as biogenesis, dynamics, and mitophagy, and is essential for maintaining cardiac function while preserving structural integrity, energy supply, and redox balance. Given their high reliance on mitochondrial adenosine triphosphate generation, cardiomyocytes are particularly vulnerable to mitochondrial dysfunction. In the cardiovascular system, mitochondria respond to various pathophysiological conditions, such as ischemia-reperfusion injury, hypertension, diabetic cardiomyopathy, and heart failure. Mitochondrial impairment drives cardiovascular disease progression through deficient energy production, elevated oxidative stress, activation of inflammatory responses, and programmed cell death. Growing evidence highlights the critical roles of epigenetic and transcriptional networks in the coordinated regulation of mitochondrial biogenesis and metabolism. Targeting these processes is a promising therapeutic strategy to improve mitochondrial health in cardiovascular diseases. This review systematically summarizes recent advances, outlines the key regulatory mechanisms of mitochondrial biogenesis and metabolism, and explores their pathophysiological roles and therapeutic potential.

As a noninvasive brain stimulation technique, transcranial alternating current stimulation (tACS) can stimulate cortical neurons with sinusoidal and biphasic alternating current, which is expected to become an innovative neuromodulatory intervention for brain-related diseases. tACS primarily modulates the synchronization and desynchronization of neuronal electrical activity through low-intensity alternating current at specific frequencies, which regulates cortical excitability, alters endogenous cortical rhythms, and subsequently influences brain function. In recent years, tACS technology has been applied in clinical studies targeting various psychiatric and neurological disorders, demonstrating preliminary progress. However, the current research has focused mainly on feasibility studies and case analyses, while the effectiveness and safety of tACS modulation strategies require rigorous scientific validation. In the future, it will be necessary to conduct more high-quality, multicenter, large-sample randomized controlled double-blind trials targeting the different dysfunctions of patients with neuropsychiatric disorders and screen for optimal treatment parameters and stimulation sites to achieve the best neuromodulation effect. This article reviews the potential mechanisms, research progress, and factors influencing the therapeutic efficacy of tACS in the treatment of neuropsychiatric disorders. Furthermore, we discuss the existing challenges and future development trends in this field, aiming to provide novel insights and strategies for the clinical treatment and scientific investigation of neuropsychiatric disorders.

The treatment paradigm for lymphoma, a highly heterogeneous group of hematologic malignancies, has been revolutionized by the development of therapies targeting oncogenic signaling pathways. This shift from conventional chemotherapy to precision medicine is driven by a deep molecular understanding of the pathways that govern lymphoma cell survival and proliferation. This review comprehensively surveys the landscape of these targeted therapies, from fundamental molecular mechanisms to clinical breakthroughs. We first dissect the molecular architecture of key oncogenic drivers, covering foundational survival networks such as the B-cell receptor, phosphatidylinositol 3-kinase /protein kinase B/mammalian target of rapamycin, Janus kinase/signal transducer and activator of transcription, and B-cell lymphoma 2 apoptosis pathways; critical regulatory processes like nuclear export controlled by exportin 1 and epigenetic patterns. For each therapeutic class, we discuss the clinical development of specific inhibitors and the challenge of acquired resistance. Furthermore, we examine emerging concepts in lymphoma, including the context-dependent role of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway, to provide a comprehensive overview of the current therapeutic landscape. A central theme of this review is the integration of these targeted agents into clinical practice. We discuss how the successful targeting of oncogenic signaling pathways has enabled the development of effective chemotherapy-free regimens, which offer durable responses with reduced toxicity and improved quality of life. Although initially transformative for patients with indolent lymphomas or those unfit for intensive chemotherapy, this paradigm is now extending to aggressive lymphomas as well. Another pivotal advance is the use of molecular subtyping and predictive biomarkers to guide treatment. As powerfully demonstrated by recent clinical trials, aligning targeted agents with the specific signaling or epigenetic dependencies of a tumor subtype can significantly enhance the efficacy of standard immunochemotherapy backbones in both B-cell and T-cell lymphomas. Finally, we address the persistent challenges of acquired resistance and discuss future directions, including the development of next-generation agents such as proteolysis-targeting chimeras, the design of rational, synergistic combination strategies, and the leveraging of multiomics and artificial intelligence to decipher complex signaling networks. By continuing to translate molecular insights into clinical practice, the field is steadily moving toward the goal of achieving precision cures for patients with lymphoma.

Epidermal growth factor receptor (EGFR) is a critical driver gene in non-small cell lung cancer (NSCLC). Since 1997, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have evolved from first-generation agents, such as gefitinib, erlotinib, and icotinib, to second-generation agents like afatinib and dacomitinib, now to third-generation agents, including osimertinib, aumolertinib, furmonertinib, befotertinib, rezivertinib, rilertinib, limertinib, lazertinib, mifanertinib for EGFR L858R, sunvozertinib for EGFR exon 20 insertion (20ins), and zorifertinib for EGFR-sensitive mutation with brain metastases. Throughout this evolution, EGFR-TKIs have become the cornerstone of treatment for EGFR-mutant NSCLC, extending beyond advanced stages to encompass the entire disease spectrum, including perioperative and maintenance therapies, with combination therapies further expanding treatment options. These advancements have significantly improved patient survival and quality of life. However, challenges such as acquired resistance remain significant hurdles in achieving long-term disease control. Over the past 30 years, substantial advancements have been made in the comprehensive management of EGFR-mutant NSCLC. This systemic review provides the history of the development of EGFR-TKI therapy for NSCLC from 1997 to 2026, highlighting clinical milestones, emerging therapies, and future directions in this rapidly evolving field.

Background: Hematological malignancies are a heterogeneous group of diseases caused by disruptions in normal hematopoietic function. This study aimed to evaluate the global burden of hematological malignancies, including Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and leukemia, with a focus on comparing China and the United States (US). Methods: Data from the GLOBOCAN 2022 and Global Burden of Disease (GBD) 2021 were used to estimate the incidence and mortality of hematological malignancies. This study analyzed the age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and estimated annual percentage change (EAPC) to compare trends over time, and risk factors were also assessed. Results: In 2022, there were 1,311,104 new cases and 700,205 deaths from hematological malignancies worldwide. Among them, there were 197,438 new cases and 110,367 deaths in China, whereas in the US, there were 181,894 new cases and 58,283 deaths. NHL was the most common type of hematological malignancy, followed by leukemia, MM, and HL globally. Males had higher incidence and mortality rates than females. Compared with China, the US had higher ASIR (30.65 vs. 9.51 per 100,000) and ASMR (7.33 vs. 4.73 per 100,000) in 2022. Additionally, the ASIR and ASMR were higher in very high human development index (HDI) countries than in low HDI countries. The incidence of NHL and MM has increased over time, whereas the incidence of HL and leukemia has decreased worldwide. The ASMRs for all types of hematological malignancies, except for MM, have been declining. Furthermore, we identified risk factors contributing to hematological malignancy disability-adjusted life years (DALYs) and deaths, including smoking, high body mass index, and occupational exposure to benzene or formaldehyde. The predicted number of new cases of and deaths from hematological malignancies gradually increased from 2022 to 2050. Conclusions: This study highlights the serious burden of hematological malignancies worldwide, in China, and in the US, emphasizing the urgency for effective prevention and treatment strategies.

Background: Topical finasteride is a novel treatment for men with androgenetic alopecia (AGA). This study aimed to evaluate the efficacy and safety of topical finasteride spray solution in Chinese men with AGA. Methods: This randomized, double-blind, placebo-controlled, phase III trial enrolled 270 individuals with AGA from 16 sites across China between December 2021 and March 2023. The participants were randomized at a ratio of 2:1 to receive either topical finasteride or placebo treatment once daily for 24 weeks. The primary endpoint was the change from baseline in target area (0.903 cm2 area) hair count at week 24. The secondary endpoints were change from baseline in target area hair count at week 12, target area terminal hair count at weeks 12 and 24, target area terminal hair width at week 24, and target area hair width at week 24; an improvement of vertex hair growth assessed by the investigator at week 24; and the patient-assessed scores on the Male Hair Growth Questionnaire at week 24. Results: A total of 270 individuals were enrolled and randomized, and 251 completed the study (165 in topical finasteride group, 86 in placebo group). Compared with the placebo group, in the topical finasteride group, the change from baseline in target area hair count was significantly higher at week 24 (P <0.05), although it was only numerically higher at week 12 (P = 0.0688). Significant differences favoring topical finasteride over placebo were observed for change from baseline in target area terminal hair count at weeks 12 (P <0.05) and 24 (P <0.01). The improvement of vertex hair growth assessed by the investigator was significantly greater in the topical finasteride group vs. the placebo group at week 24 (P <0.01). Topical finasteride was generally safe and well-tolerated. Conclusions: In Chinese men with AGA, topical finasteride spray solution increased hair growth and showed good safety and tolerability profile during a 24-week treatment period.

Background: Metabolic-associated steatotic liver disease (MASLD) is a heterogeneous condition with highly variable outcomes. We aimed to distinguish the subtypes of MASLD that were associated with varying risks of hepatic and extrahepatic outcomes. Methods: An innovative multi-task deep least absolute shrinkage and selection operator (LASSO) algorithm was developed for feature selection in the discovery cohort (n = 1111, 87.6% [973/1111] of biopsy-proved MASLD), followed by clustering analysis in MASLD. Validation was performed in 6172 individuals who undertook health check-ups (MASLD: 43.9% [2710/6172], mean follow-up 27.6 months) and 7406 participants from the Third National Health and Nutrition Examination Survey (NHANES III) (MASLD: 37.3%, mean follow-up 280.2 months). Results: Four clusters with distinct risks of hepatic and extrahepatic outcomes were identified in the discovery cohort: Cluster 1 characterized by subcutaneous adiposity, modest metabolic disorders, but lower risk of cardiovascular disease (CVD); Cluster 2 characterized by significant hyperlipidemia, substantial liver damage, and increased hepatic fibrosis risk; Cluster 3 characterized by low muscle mass, remarkable chronic systemic inflammation, and a higher risk of cardiovascular-kidney complications; and Cluster 4 characterized by severe insulin resistance, visceral adiposity, poor glucose and lipid control, and severe liver damage, conferring a high risk of cardiovascular-liver-kidney complications. Additionally, Cluster 4 exhibited the highest frequencies of PNPLA3 risk alleles. The prognostic relevance was further confirmed in external validation cohorts. Specifically, Clusters 3 and 4 had increased risks of all-cause and CVD-related mortality. Conclusions: We developed a novel algorithm that identified four MASLD clusters, each characterized by distinct clinical features and varying risks of hepatic and extrahepatic outcomes. This classification facilitates the precise integration of MASLD risk stratification and management within the cardiovascular-liver-kidney-metabolic framework.

Background: Intron retention (IR) is an important biological process associated with disease development. However, the role of IR in the progression of tuberculosis (TB) remains unexplored. Therefore, this study aimed to characterize the dynamic IR landscape during TB progression and elucidate the role of DNASE1L2-IR in this process. Methods: We conducted a comprehensive high-throughput sequencing analysis using 1729 samples from 19 public datasets and identified candidate IR events associated with TB progression. We then validated these candidate IR events in three macrophage infection models by quantitative polymerase chain reaction and revealed the underlying molecular mechanisms by investigating the subcellular localization and functional roles of their associated isoforms. Results: In an analysis of 1729 clinical specimens, we found genome-wide intron-splicing reprogramming in host cells during TB progression. Notably, deoxyribonuclease 1 like 2 (DNASE1L2, a gene encoding deoxyribonuclease)-IR exhibited striking differences among healthy controls, individuals with latent TB infection, and individuals with active TB (Padj <0.05), particularly between progressors and nonprogressors (Padj <0.0001). Similar differences were observed in Mycobacterium tuberculosis (M. tuberculosis) infection models in vitro; as the stimulation increased in concentration or duration, IR initially increased but subsequently decreased. DNASE1L2-IR generated two transcript isoforms: a long isoform (DNASE1L2-L) and a short isoform (DNASE1L2-S). Upon stimulation, DNASE1L2-L appeared in the cytoplasm, whereas DNASE1L2-S remained membrane-anchored. Deoxyribonuclease activity assays revealed that compared with DNASE1L2-S, DNASE1L2-L exhibited significantly greater enzymatic activity against plasmid and M. tuberculosis DNA substrates and more effectively suppressed the release of interleukin-1beta and tumor necrosis factor alpha, indicating isoform-specific functional divergence in inflammatory regulation. Conclusion: These findings identify DNASE1L2-IR splicing dynamics as a novel biomarker for monitoring TB progression and reveal a host-defense mechanism in which DNASE1L2-IR regulates M. tuberculosis DNA degradation to modulate TB progression.

Background: Endometrial cancer (EC) is one of the most common gynecological cancers worldwide. High-order chromatin structure plays a critical role in regulating gene expression. Our previous study identified frequent mutations in the chromatin remodeling-related gene adenomatous polyposis coli (APC) in EC. Here, we investigated the role of APC in chromatin remodeling and EC progression. Methods: The efforts of APC against EC cells in vitro and in vivo were characterized by gene expression and overall survival analysis with The Cancer Genome Atlas (TCGA) database, Western blotting, RNA isolation and quantitative real-time polymerase chain reaction (RT-PCR), the integrated multiomics analysis, lentivirus transfection, nude mice tumorigenesis experiment, and immunohistochemistry. Results: APC expression was reduced in EC tissues, and APC-knockdown KLE cells exhibited enhanced cell migration. Integrated multi-omics analyses, including RNA sequencing (RNA-seq), assay for transposase-accessible chromatin by high-throughput sequencing (ATAC-seq), and high-through chromosome conformation capture (Hi-C), compared control and APC-knockdown KLE cells. These analyses identified fibroblast growth factor 12 (FGF12) as a differentially expressed gene (DEG) localized to switched chromatin compartments, cell-specific boundaries, and loops, with elevated expression in APC-knockdown cells. High FGF12 expression correlated with poor prognosis in EC patients. Knockdown of FGF12 in APC-deficient KLE cells reversed the enhanced migratory phenotype. Conclusions: Loss of APC promotes EC cell migration and reprograms chromatin architecture to upregulate FGF12, activating tumorigenesis-related protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways and driving EC progression. Elevated FGF12 levels are associated with poor prognosis, highlighting its potential as a therapeutic target for EC patients with low APC expression.